Use of ylides of phosphorus as slightly nuceophilic strong bases

ABSTRACT

In a process for C-alkylation or N-alkylation, the improvement comprising conducting the C-alkylation or N-alkylation reaction in the presence of a slightly nucleophilic strong base of the following formula                    
     wherein R′ 1 , R′ 2  and R′ 3  are individually selected from the group consisting of alkoxy of 1 to 6 carbon atoms and                    
     R′ and R″ are individually selected from the group consisting of unsubstituted or substituted alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl and aralkyl of 1 to 6 alkyl carbon atoms, the substituents being selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO 2  and dialkylamino of 1 to 6 alkyl carbon atoms, the aryl being selected from the group consisting of unsaturated monocyclic and condensed carbocyclic and heterocyclic with at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, R′ 4  is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms and R′ 5  is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and a polymeric support.

This application is a 371 of PCT Application No. FR98/01048 filed on May26, 1998, now WO 98/54229.

The present invention relates to the use of phosphorus ylides asslightly nucleophilic strong bases. The invention also relates to newphosphorus ylides and their preparation.

Strong organic bases are generally necessary to functionalize organic ororganometallic molecules; and the stronger the base, the better it trapsthe protons. In order to limit parasitic reactions, it is preferable andeven desirable to choose a base which is only slightly nucleophilic.Moreover, the ease with which the acid obtained is separated from thereaction medium is a determinant factor in order to simplify thepurification stages.

Phosphorus ylides were studied by Wittig in the 1950's (Johnson, A. W.,1993, Series, Editor, Ylides and Imines of phosphorus, Wiley & Wiley:New York). These molecules are quite simple and even if some arepresented as colorants (U.S. Pat. No. 3,274,228), they are usuallyprepared to be used for Wittig's reaction (U.S. Pat. Nos. 3,681,428,3,725,365) where their strong nucleophilic action is involved. But thesecompounds have never been used as bases in organic synthesis, and afortiori as slightly nucleophilic strong bases.

The strong neutral organic bases known to date are essentially protonsponges (Alder, R. et al., J. Chem. Soc. Chem. Commun., 1968, 723),guanidines, phosphatranes and polyphosphazenes.

Guanidines constitute the class of strong organic bases most frequentlyused in organic synthesis. The best known are DBN (1,5-diazabicyclo[4.3.0] non-5-ene) and DBU (1,8-diazabicyclo [4.3.0] undec-5-ene). Otherguanidines are also mentioned in the literature (Oediger, H. et al.,Synthesis, 1972, 593; Schwesinger, R., Angew. Chem. Int. Ed. Eng., 1987,26, 1164). These bases are used in elimination reactions or inoligomerization or polymerization processes as a reaction initiator(Oediger, H. et al., Synthesis, 1972, 593; Wöhrle, D. et al., Dyes andPigments, 1992, 18, 91).

Phosphatranes are more recent compounds (Verkade, J., 1991,Phosphatranes as proton abstracting reagents, U.S. Pat. No. 5,051,533).Their basicity is much greater than that of guanidines, which extendstheir field of application. The drawback of such phosphines lies in thedifficulty in obtaining them and their purification.

As regards polyphosphazenes, recently developed by Schwesinger, theseare the most basic organic molecules demonstrating a very slightnucleophilic action. They are however very difficult to synthesize andtheir cost is very high (Schwesinger, R. et al., Liebigs Ann., 1996,1055; Schwesinger, R. et al., Angew. Chem. Int. Ed. Engl., 1991, 30,1372; Schwesinger, R. et al., Angew. Chem. Int. Ed. Engl., 1987, 26,1167; Schwesinger, R. et al., Angew. Chem. Int. Ed. Engl., 1987, 26,1165; Schwesinger, R., Chimia, 1985, 39, 269). Their uses are veryvaried: they range from simple elimination to the benzylation ofoligopeptides (Schwesinger, R., Chimia, 1985, 39, 269; Pietzonka, T. etal., Angew. Chem. Int. Ed. Engl., 1992, 31, 1481). The basicity of thesemolecules is sufficient to remove the slightly acidic protons and theirorganic character avoids the undesirable effects of salts in certainalkylations (Pietzonka, T. et al., Chem. Ber., 1991, 124, 1837).

Alkaline bases such as BuLi, LiHMDS, NaHMDS, LDA also represent anotherlarge family of bases. They are often used with good yields tofunctionalize lactames, ketones or Schiff bases (Stork, G. et al., J.Org. Chem., 1976, 41, 3491; Myers, A. et al., J. Am. Chem. Soc., 1994,116, 9361; Myers, A. et al., J. Am. Chem. Soc., 1995, 117, 8488;Yaozhong, J. et al., Synth. Commun., 1990, 20, 15; Butcher, J.,Liverton, N., Selnick, H., Helliot, J., Smith, G., et al., Tet. Lett.,1996, 37, 6685; Davis, F., Sheppard, A. et al., J. Am. Chem. Soc.,1990). The effects of salts are very frequent and often vary from onereaction to another and these bases retain a strong nucleophiliccharacter even at low temperatures. (Meyers, A., Kunnen, K., .J Am.Chem. Soc., 1987, 109, 4405).

The problem is therefore to find slightly nucleophilic strong bases,which are easy to synthesize and at a low cost, which would besusbstituted on the one hand for commonly used bases which are toonucleophilic and on the other hand for recent bases which are tooexpensive.

The invention therefore relates to the use of products of generalformula I′

in which

R′₁, R′₂ and R′₃ represent, independently, a lower alkoxy or aminoradical of formula R′R″N in which R′ and R″ independently represent oneof the following radicals, non-substituted or substituted (by one ormore identical or different substituents): lower alkyl, lower alkoxy,cycloalkyl, lower aryl-alkyl, aryl, in which the substituent is ahalogen atom or a lower alkyl, lower alkoxy, cyano, nitro ordialkylamino radical;

R′₄ represents the hydrogen atom, a lower alkyl radical or lower alkoxy;

R′₅ represents the hydrogen atom, a lower alkyl radical, lower alkoxy ora polymeric support;

as a slightly nucleophilic strong base.

In the definitions indicated above, the expression halogen represents afluorine, chlorine, bromine or iodine atom, preferably chlorine orbromine. The expression lower alkyl represents a linear or branchedalkyl radical having 1 to 6 carbon atoms and in particular an alkylradical having 1 to 4 carbon atoms such as the methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl radicals.

The lower alkoxy radicals can correspond to the alkyl radicals indicatedabove. Among the linear radicals, there can be mentioned the methoxy,ethoxy, propyloxy, n-butyloxy or n-hexyloxy radicals. Among the branchedalkoxy radicals, there can be mentioned the isopropyloxy, sec-butyloxy,isobutyloxy, ter-butyloxy, isopentyloxy, neopentyloxy or ter-pentyloxyradicals.

The term cycloalkyl includes any non-aromatic cyclic hydrocarbonfragment having 3 to 10 carbon atoms and preferably cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

The term aryl designates radicals which are unsaturated, monocyclic orconstituted by condensed rings, carbocyclic or heterocyclic, it beingunderstood that the heterocyclic radicals can include one or moreidentical or different heteroatoms chosen from oxygen, sulphur ornitrogen. Examples of such groups include the phenyl, thienyl, furyl,pyridyl, pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl,triazolyl, thiatriazolyl, oxazolyl, benzothienyl, benzofuryl,benzopyrrolyl, benzimidazolyl, benzaxozolyl, indolyl, purinyl, naphthyl,thionaphthyl, phenanthrenyl, anthracenyl, biphenyl, indenyl, quinolyl,isoquinolyl or quinolizinyl radicals. The lower arylalkyl radicalsdesignate the radicals in which the aryl and lower alkyl radicalsrespectively are as defined above such as for example benzyl, phenethylor naphthylmethyl.

The term dialkylamino represents the amino radical substituted by twoalkyl radicals, identical or different, as defined above, such as forexample dimethylamino, (methyl)(ethyl)amino, diethylamino.

The expression slightly nucleophilic means non nucleophilic with respectto other centres than protons. The term strong base corresponds to theterm commonly used by a person skilled in the art in the technical fieldconsidered. The polymeric support can be, for example, of methacrylic,acrylic or styrenic type.

The invention relates more particularly to the use, as a slightlynucleophilic strong base, of products of general formula I′ as definedabove characterized in that R′₁, R′₂ and R′₃ represent, independently,an amino radical of formula RR′N as defined above. Preferably, R′₁, R′₂and R′₃ represent, independently, the dimethylamino,(methyl)(ethyl)amino or diethylamino radical.

The invention relates more particularly to the use, as a slightlynucleophilic strong base, of products of general formula I′as definedabove characterized in that R′₄ represents the hydrogen atom or an alkylradical. Preferably, R′₄ represents the hydrogen atom or the methyl orethyl radical.

The invention also relates more particularly to the use, as a slightlynucleophilic strong base, of products of general formula I′as definedabove characterized in that R′₅ represents an alkyl radical, andpreferably methyl, or a polymeric support. Preferentially, the polymericsupport R′₅ is of methacrylic type, acrylic type such as the expansine®polymer, or polystyrenic type. Preferably, the polymeric support ofpolystyrenic type is of general formula (s)

in which n_(i), m_(i) and q_(i) are integers greater than or equal toone.

The polymeric support of formula (s) can originate from thecorresponding polymer of formula (p)

in which n, n′, m are integers greater than or equal to one and Xrepresents a parting group. As a parting group, X can be, for example, ahalogen atom, the oxycarbonyl, oxysulphonyl or oxyboronyl radical.Preferably, the polymeric support R′₅ originates from a polystyrenicpolymer of general formula (p) as defined above in which X representsthe chlorine atom and m is equal to 1, and more particularly Merrifieldresin.

A more particular subject of the invention is the use of the compoundsof formula I′ as defined above, as slightly nucleophilic strong bases inN-alkylation reactions such as, for example, the N-alkylation reactionsof lactames, succinimides, oligopeptides and benzodiazepines.

A more particular subject of the invention is also the use of theproducts of general formula I′ as defined above as slightly nucleophilicstrong bases in C-alkylation reactions such as, for example, theC-alkylation reactions of lactames, succinimides, Schiff bases andbenzodiazepines.

A more particular subject of the invention is the use of the productscorresponding to the following formulae:

styrene/divinylbenzene-tris(dimethylamino)methylenephosphoranecopolymer;

tris(dimethylamino)-C-dimethylmethylene phosphorane.

as a slightly nucleophilic strong base, and in particular inN-alkylation or C-alkylation reactions.

Among the compounds of formula I′ as defined, certain are known(Johnson, A. W., 1993, Series, Editor, Ylides and Imines of phosphorus,Wiley & Wiley: New York).

Therefore, a subject of the invention is also new phosphorus ylides andmore particularly the products of general formula (I)

in which R₁, R₂ and R₃ represent, independently, a lower alkoxy or aminoradical of formula R′R″N in which R′ and R″ independently represent oneof the following radicals, non-substituted or substituted (by one ormore identical or different substituents): lower alkyl, lower alkoxy,cycloalkyl, lower aryl-alkyl, aryl, in which the substituent is ahalogen atom or a lower alkyl, lower alkoxy, cyano, nitro ordialkylamino radical;

R₄ represents the hydrogen atom, a lower alkyl or lower alkoxy radical;and

R₅ represents a polymeric support.

A more particular subject of the invention is the products of generalformula I as defined above characterized in that R₁, R₂ and R₃represent, independently, an amino radical of formula RR′N as definedabove. Preferably, R₁, R₂ and R₃ represent, independently, the radicaldimethylamino, (methyl)(ethyl)amino, diethylamino radical.

A more particular subject of the invention is the products of generalformula I as defined above characterized in that R₄ represents thehydrogen atom.

A more particular subject of the invention is the products of generalformula I as defined above characterized in that the polymeric supportR₅ is of methacrylic type, acrylic type such as the polymer expansine®,or polystyrenic type. Preferably, the polymeric support of polystyrenictype is of general formula (s) as defined above.

A subject of the invention is also a process for the preparation of theproducts of general formula I as defined above, characterized in that

a phosphine of general formula (1)

PR₁R₂R₃  (1)

in which R₁, R₂ and R₃ have the meaning indicated above, is reacted witha compound of general formula (2)

in which R₄ and R₅ have the meaning indicated above and Y is such thatY⁻ represents any anion, in order to obtain the product of generalformula (3)

which product (3) thus obtained is treated with a strong base in orderto obtain a product of formula I.

The preparation of compound (3), from compounds (1) and (2) ispreferably carried out under an inert atmosphere, such as for exampleunder an argon atmosphere, in a polar solvent such as1,2-dichloroethane, acetonitrile, dimethoxyethane or diethoxymethane.Compound (2) is in general in stoechiometric excess with respect tocompound (1). In this compound (2), Y is such that Y⁻ represents anyanion known to a person skilled in the art such as, for example,halides, triflate. The reaction medium is then agitated under reflux ofthe solvent. After the standard washing stages, compound (3) is driedunder vacuum. In order to obtain product (I), product (3) thus obtainedis treated, at ambient temperature, in the presence of a strong base.The strong base can be for example a lithiated base such as alkyllithium compounds, and more particularly butyllithium, a sodium orpotassium hydride, an amide or an alcoholate. The solvent can be chosenfrom pentane, ether, tetrahydrofuran, dimethoxyethane ordiethoxymethane, in which solvent the strong base is stable. The mixtureobtained is agitated for a few hours. Polymer (I) is washed under vacuumthen dried. It can then be used directly without further purification.

The compound of formula (1) in which R₄ does not represent the hydrogenatom, can be obtained by reacting the corresponding compound (I) inwhich R₄ represents the hydrogen atom, with a compound of formula R₄X′in which X′ represents a halogen atom and R₄ is as defined above butdoes not represent the hydrogen atom, at a temperature comprised between−10 and +10° C., preferably at 0° C., in a solvent such as THF. Afterfiltration and washing, the product thus obtained can be treated with astrong base in order to obtain the desired compound (I).

A subject of the invention is also, as new industrial products, and inparticular as new industrial products intended for the preparation ofproducts of formula (I), the products of formula (3) as described above.

The compounds of formula (1) and (2) are generally commercial productsand can be obtained according to standard methods known to a personskilled in the art. The compounds of formula (I′) in which R′₅represents the hydrogen atom, a lower alkyl or lower alkoxy radical, canbe prepared according to standard methods known to a person skilled inthe art (Johnson, A. W., 1993, Series, Editor, Ylides and Imines ofphosphorus, Wiley & Wiley: New York).

The following examples are presented in order to illustrate the aboveprocedures and must in no case be considered as a limit to the scope ofthe invention.

EXPERIMENTAL PART EXAMPLE 1

Preparation of a Supported Ylide

Stage 1a: Preparation of Compound (3)

7 g of Merrifield resin (1 meq/g) is placed under an inert atmosphere ofargon. A solution of 21 mmol of P(NMe₂)₃ in 100 ml of dichloroethane isadded and the reaction medium is maintained under magnetic stirring for5 days at ambient temperature. The polymer is then washed several timeswith dichloromethane in order to remove the excess phosphine. It is thendried under vacuum until the polymer mass obtained does not change anymore (8 g). Compound (3) is obtained in the form of a fine white sand.(M.p. (dec.): 325° C.).

The grafting rate is checked by the reactivity of the polymer obtained.The solvent used for the grafting can also be dimethoxyethane.

1b: Preparation of Compound (I)

1.1 mmol of butyllithium is added at ambient temperature to 1 g ofcompound (3) in suspension in 20 ml of tetrahydrofuran (THF). Themixture becomes red and heat is seen to be generated. Stirring ismaintained for one hour. 40 ml of THF is then added and the polymer isrecovered by filtration. The polymer is then washed with 40 ml of THF.The operation is repeated twice. An orange-coloured powder is thenobtained which is used directly in deprotonation reactions. After eachuse the polymer precursor (3) is reovered by filtration and can again beconverted into a supported ylide.

EXAMPLE 2

Use of the Compounds According to the Invention in a C-alkylationReaction

EXAMPLE 2a

C-benzylation of N-methyl-2-pyrrolidinone

6 mmoles of (Me₂N)₃P═C(CH₃)₂ in 27 ml of THF is added to a solution of 5mmoles of N-methyl-2-pyrrolidinone in 23 ml of THF. The solution isheated at 45° C. for 6 hours, then 6 mmoles of benzyl bromide is addedand agitation is maintained for an additional hour at 45° C. Thereaction mixture is left to slowly return to ambient temperature. Afterextraction with 60 ml of ether, filtration and evaporation of thesolvent, the oil obtained is purified on a chromatographic column(eluent: ether/methanol 95/5).

NMR ¹H (CDCl₃): 2.00 (m, 2H, CH₂); 2.63 (m, 2H, CH₂—N); 2.79 (s, 3H,CH₃—N); 3.10 (m, 3H, CH and CH₂Ph); 7.19 (m, 5H, H_(arom)).

NMR ¹³C (CDCl₃): 23.88 (s, CH₂); 29.59 (s, CH₃—N); 36.99 (s, CH₂); 43.27(s, CH); 47.39 (s, CH₂—N); 126.17, 128.28, 128.88 (s, CH_(arom)); 139.29(s, C_(ipso)); 175.72 (s, CO).

EXAMPLE 2b

C-alkylation in Position 3 of Benzodiazepines According to the FollowingDiagram

1.5 mmoles of ylide (Me₂N)₃P═C(CH₃)₂ in 7.5 ml of THF is added, at −78°C., to a solution 1 mmole of compound (B1) in 5 ml of THF. The reactionmixture is agitated for 15 minutes, then 1.5 mmoles of the compound offormula RbX′, in which X′ represents a atom of halogen and Rb representsan optionally substituted alkyl radical, are added. Agitation ismaintained for another 30 minutes. After extraction with 60 ml of ether,filtration and evaporation of the solvent, the oil is purified on achromatographic column (eluent: pentane/ether 50/50). The compound offormula (B2) is obtained in the form of a powder.

The results obtained according to the value of Ra and Rb are summarizedin the table below.

Ex Ra Rb Yield (%) 2b₁ —CH₂Ph —CH₂Ph 38 2b₂ —CH₂Ph —CH₂CO₂tBu 42 2b₃—CH₂Ph —CH₃ 67 2b₄ —CH₃ —CH₂Ph 55 2b₅ —CH₃ —CH₂CO₂tBu 42 2b₆ —CH₃ —CH₃43 2b₇ —CH₂CO₂tBu —CH₂CO₂tBu 48 2b₈ —CH₂CO₂tBu —CH₂Ph 39 2b₉ —CH₂CO₂tBu—CH₃ 54

Characteristics of the Compounds

EXAMPLE 2b₁

melting point 87° C.

NMR ¹H (CDCl₃): 3.65 (m, 2H, CH₂Ph); 3.87 (m, 1H, CH); 4.68 (d,²J_((HH))=15.3 Hz, 1H, N—CH₂Ph); 5.68 (d, ²J_((HH))=15.3 Hz, 1H,N—CH₂Ph); 7.20 (m, 18H, H_(arom)).

NMR ¹³C (CDCl₃): 37.95 (s, CH—CH₂Ph); 49.95 (s, N—CH₂Ph); 65.27 (s,CH—CH₂Ph); 123,92-131.24 (s, CH_(arom)); 129.43, 131.99, 136.27, 137.94,138.99, 140.05 (s, Cq); 167.43; 169.05 (s, CO and CN).

EXAMPLE 2b₂

melting point 166° C.

NMR ¹H (CDCl₃): 1.47 (s, 9H, CH₃); 3.25 (dd, ²J_((HH))=16.9 Hz,²J(HH)=7.5 Hz, H_(B), CH₂); 3.43 (dd, ²J_((HH))=16.9 Hz, ²J_((HH))=6.5Hz, H_(B), CH₂); 4.19 (dd, ³J_((HH))=7.6 Hz, ³J_((HH))=6.5 Hz, H_(A),CH); 4.75 (d, ²J_((HH))=15.5 Hz, H_(A), N—CH₂ Ph); 5.60 (d,²J_((HH))=15.5 Hz, H_(B), N—CH₂ Ph); 6,97-7.43 (m, 13H, H_(arom)).

NMR ¹³C (CDCl₃):28.14 (s, CH₃); 37.80 (s, CH₂COOtBu); 50.28 (s,N—CH₂Ph); 60.62 (s, CH); 80.70 (s, Cq(CH₃)₃); 124,01-131.38 (s,CH_(arom)); 129.54; 132.11; 136.20; 137.90; 140.31 (s, Cq); 167.50;169.02; 171.30 (s, CO, CN and COO).

EXAMPLE 2b₃

melting point 164° C.

NMR ¹H (CDCl₃): 1.77 (d, ³J_((HH))=6.4 Hz, 3H, CH₃); 3.81 (q,³J_((HH))=6.4 Hz, 1H, CH); 4.68 (d, ²J_((HH))=15.5 Hz, H_(A), CH₂ Ph);5.70 (d, ²J_((HH))=15.5 Hz, H_(B), CH₂ Ph); 6,99-7.42 (m, 13H,H_(arom)).

NMR ¹³C (CDCl₃): 17.32 (s, CH₃); 49.82 (s, CH₂Ph); 58.81 (s, CH);123,94-131.30 (s, CH_(arom)); 130.38; 131.07; 136.39; 137.93; 140.20 (s,Cq); 167.16; 170.35 (s, CO and CN).

EXAMPLE 2b₄

melting point 85° C.

NMR ¹H (CDCl₃): 3.40 (s, 3H, N—CH₃); 3,56-3.77 (m, 3H, CH and CH₂Ph);7,19-7.55 (m, 13H, H_(arom)).

NMR ¹³C (CDCl₃): 35.28 (s, N—CH₃); 38.10 (s, CH₂Ph); 65.27 (s, CH);122,77-131.45 (s, CH_(arom)); 129.16; 130.32; 138.15; 139.21; 142.15 (s,Cq); 168.01; 170.05 (s, CO and CN).

EXAMPLE 2b₅

melting point 141° C.

NMR ¹H (CDCl₃): 1.45 (s, 9H, CH₃); 3.40 (s, 3H, N—CH₃); 3.11 (dd,²J_((HH))=17.1 Hz, ²J_((HH))=7.0 Hz, H_(B), CH₂); 3.39 (dd,²J_((HH))=17.1 Hz, ²J_((HH))=6.8 Hz, H_(B′), CH₂); 4.07 (dd,³J_((HH))=7.0 Hz, ³J_((HH))=6.8 Hz, H_(A), CH); 7,25-7.57 (m, 8H,H_(arom)).

NMR ¹³C (CDCl₃): 28.12 (s, CH₃); 35.21 (s, N—CH₃); 37.91 (s, CH₂); 60.56(s, CH); 80.59 (s, C_(q)(CH₃)₃); 122,83-130.36 (s, CH_(arom)); 131.52;137.97; 139.40; 142.20 (s, C_(q)); 167.20; 169.70; 171.25 (s, CO, CN andCOO).

EXAMPLE 2b₆

melting point 76° C.

NMR ¹H (CDCl₃): 1.71 (d, ³J_((HH))=6.5 Hz, 3H, CH₃); 3.39 (s, 3H,N—CH₃); 3.70 (q, ³J_((HH))=6.5 Hz, CH); 7,25-7.60 (m, 8H, H_(arom)).

NMR ¹³C (CDCl₃): 17.43 (s, CH₃); 35.15 (s, N—CH₃); 58.90 (s, CH);122,59-130.54 (s, CH_(arom)); 129.11; 129.63; 131.38; 138.13 (s, Cq);166.85; 171.21 (s, CO and CN).

EXAMPLE 2b₇

melting point 128° C.

NMR ¹H (CDCl₃): 1.40 (s, 9H, CH₃); 1.44 (s, 9H, CH₃); 3.14 (dd,²J_((HH))=16.9 Hz, ²J_((HH))=6.8Hz, 1H, H_(B)); 3.43 (dd, ²J_((HH))=16.9Hz, ²J_((HH))=7.0 Hz, 1H, H_(B′)); 4.15 (dd, ³J_((HH))=7.0 Hz,³J_((HH))=6.8 Hz, 1H, H_(A)); 4.20 (d, ²J_((HH))=17.1 Hz, 1H,CH₂COOtBu); 4.48 (d, ²J_((HH))=17.1 Hz, 1H, CH₂COOtBu); 7,25-7.60 (m,8H, H_(arom)).

NMR ¹³C (CDCl₃): 27.90; 28.06 (s, CH₃); 7.82 (s, CH₂); 50.81 (s, N—CH₂);60.33 (s, CH); 80.61; 82.43 (s, Cq(CH₃)₃); 123,02-131.64 (s, CH_(arom));129.89; 130.60; 130.98; 138.08 (s, Cq); 67.39; 167.76; 170.92 (s, CO, CNand COO).

EXAMPLE 2b₈

melting point 81° C.

NMR ¹H (CDCl₃): 1.41 (s, 9H, CH₃); 3.72 (m, 3H, CH and CH₂Ph); 4.40 (d,²J_((HH))=16.7 Hz, 1H, CH₂COOtBu); 4.52 (d, ²J_((HH))=16.7 Hz, 1H,CH₂COOtBu); 7,20-7.58 (m, 13H, H_(arom)).

NMR ¹³C (CDCl₃): 27.79 (s, CH₃); 37.69 (s, CH₂Ph); 50.77 (s,N—CH₂COOtBu); 64.72 (s, CH); 82.33 (s, Cq(CH₃)₃); 122,69-131.45 (s,CH_(arom)); 130.68; 131.10; 138.10; 138.91; 141.08 (s, Cq); 167.30;167.47; 169.49 (s, CO, CN and COO).

EXAMPLE 2b₉

melting point 152° C.

NMR ¹H (CDCl₃): 1.41 (s, 9H, CH₃); 1.70 (d, ³J_((HH))=6.4 Hz, 3H, CH—CH₃); 3.77 (q, ³J_((HH))=6.4 Hz, 1H, CH—CH₃); 4.23 (d, ²J_((HH))=17.2 Hz,1H, CH₂COOtBu); 4.51 (d, ²J_((HH)=)17.2 Hz, 1H, CH₂COOtBu); 7,21-7.60(m, 8H, H_(arom)).

NMR ¹³C (CDCl₃): 17.16 (s, CH₃); 27.81 (s, CH—CH₃); 50.65 (s, CH₂);58.46 (s, CH); 82.25 (s, Cq(CH₃)₃); 122,29-131.37 (s, CH_(arom));129.41; 130.82; 138.04; 141.18 (s, Cq); 167.04; 167.59; 170.50 (s, CO,CN and COO).

Examples 2a and 2b can also be implemented using a supported ylide asdefined in the present invention, and more particularly with a polymerof formula (a) as defined above in which m>1.

EXAMPLE 2c

C-alkylation in Position 3 of Benzodiazepines According to the FollowingDiagram

1 g of supported ylide as prepared according to Example 1 is agitated in20 ml of THF. A solution of 0.7 mmole of compound (C1) in 10 ml of THFis added and the reaction mixture is maintained under agitation for 30minutes, then 1 mmole of distilled benzyl bromide is added and thereaction mixture is heated at 60° C. for 12 hours. The solution is thenseparated from the polymers, the solvents are evaporated off undervacuum and compound (C2), identical to compound B2 of Example 2b4, isrecovered in the form of an orange powder with a yield of 20%.

EXAMPLE 2d

C-alkylation of Benzodiazepines in Position 3 Using an Aldehyde

1.5 mmoles of ylide (Me₂N)₃P═C(CH₃)₂ in 7.5 ml of THF is added at −78°C., to a solution of 1 mmole of compound (D1) in 5 ml of THF. Thereaction mixture is agitated for 15 minutes, then 1.5 mmoles of ethanalis added. Agitation is maintained for another 30 minutes. Afterextraction with 60 ml of ether, filtration and evaporation of thesolvent, the oil is purified on a chromatographic column (eluentpentane/ether 9515). The compound of formula (D2) is obtained in theform of a powder (44%).

EXAMPLE 3

Use of the Compounds According to the Invention in an N-alkylationReaction

EXAMPLE 3a

N-functionalization of Norvalium

1 g of the supported ylide as prepared according to Example 1 isagitated in 20 ml of THF. A solution of 0.8 mmole of norvalium in 10 mlof THF is added and the mixture is maintained under agitation for 30minutes. 1 mmol of distilled electrophilic reagent of formula RX′ isadded in which X′ represents a halogen atom and R represents anoptionally substituted alkyl radical or SiMe₃, and the mixture is leftunder agitation for 4 hours. The solution is then separated from thepolymers, the solvents are evaporated off under vacuum and the oilobtained is taken up in the solvents indicated below. For its part, thepolymer is washed and can be re-used later.

Ex RX′ Solvent Yield (%) 3a₁ Me₃SiCl Pentane 80 3a₂ BrCH₂CO₂tBu Et₂O 703a₃ PhCH₂Br Et₂O 76

EXAMPLE 3a₁

NMR ¹H (CDCl₃): 0.30 (s, 9H, CH₃); 4.10 (broad s, 2H, CH₂); 7.30 (m, 8H,H_(arom)).

NMR ¹³C (CDCl₃): −0.15 (s, CH₃); 53.71 (s, CH₂); 127,62-128.11 (s, Cq);129,63-130 CH _(arom)); 169.50; 169.52 (s, CO and CN).

EXAMPLE 3a₂

NMR ¹H (CDCl₃): 1.40 (s, 9H, CH₃); 3.80 (d, ²J_((HH))=10.7 Hz, 1H, CH₂);4.21 (d, ²J_((HH))=15.0 Hz, 1H, CH₂COOtBu); 4.45 (d, ²J_((HH))=15.0 Hz,1H, CH₂COOtBu); 4.85 (d, ²J_((HH))=10.7 Hz, 1H, CH₂); 7.40 (m, 8H,H_(arom)).

NMR ¹³C (CDCl₃): 27.65 (s, CH₃); 51.03 (s, CH₂—COOtBu); 51.03 (s,CH₂—COOtBu); 55.88 (s, CH₂); 83.50 (s, Cq(CH₃)₃); 123,63-131.98 (s,CH_(arom)); 130.23; 130.64; 137.85; 140.56 (s, C_(ipso)); 168.30;170.26; 170.58 (s, CO, COO and CN).

EXAMPLE 3a₃

NMR ¹H (CDCl₃): 1.41 (s, 9H, CH₃); 3.80 (d, ²J_((HH))=10.5 Hz, 1H, CH₂);4.23 (d, ²J_((HH))=17.2 Hz, 1H, CH₂COOtBu); 4.51 (d, ²J_((HH))=17.2 Hz,1H, CH₂COOtBu); 4.96 (d, ²J_((HH))=10.5 Hz, 1H, CH₂); 7,21-7.60 (m, 8H,H_(arom)).

NMR ¹³C (CDCl₃): 17.16 (s, CH₃); 27.81 (s, CH—CH₃); 50.65 (s, CH₂);58.46 (s, CH); 82.25 (s, Cq(CH₃)₃); 122,29-131.37 (s, CH_(arom));129.41; 130.82; 138.04; 141.18 (s, Cq); 167.04; 167.59; 170.50 (s, CO,CN and COO).

EXAMPLE 3b

N-alkylation of Lactames

A solution of 3.6 mmoles of (Me₂N)₃P═C(CH₃)₂ in 17 ml of THF is addedslowly, at 25° C., to a solution of 3 mmoles of substrate in 14 ml ofTHF. The reaction mixture is agitated at 25° C. for one hour, then 3.6mmoles of distilled electrophilic reagent of formula RX′ in which X′represents a halogen atom and R represents an optionally substitutedalkyl radical, are added. Agitation is maintained for 3 more hours. Thesupernatant solution is separated from the phosphonium salts formed byextraction with 60 ml of ether. After concentration, the oil obtained ispurified on a chromatographic column.

RX′ Eluent Yield (%) CH₃I Et₂O/MeOH 85/15 60 BrCH₂CO₂tBu Et₂O 70 PhCH₂BrEt₂O/MeOH 30/70 71

Characterization of the N-alkylated Lactame:

R═CH₃—

NMR ¹H (CDCl₃): 1.82 (m, 4H, CH₂—CH₂); 2.47 (m, 2H, CH₂—CO); 2.98 (s,3H, CH₃—N); 3.31 (m, 2H, CH₂—N).

I.R. (CDCl₃): 1642 cm⁻¹ (CO).

R═tBuOC(O)CH₂—

NMR ¹H (CDCl₃): 1.43 (s, 9H, CH₃); 1.80 (m, 4H, CH₂—CH₂); 2.55 (m, 2H,CH₂—CO); 3.35 (m, 2H, CH₂—N); 4.09 (s, 2H, CH₂—COO).

NMR ¹³C (CDCl₃): 20.44; 22.42 (s, CH₂); 27.73 (s, CH₃); 31.72 (s,CH₂—CO); 49.21; 49.90 (s, CH₂—N); 82.49 (s, C(CH₃)₃); 168.59; 172.37 (s,CO).

R═PhCH₂—

NMR ¹H (CDCl₃): 1.70 (m, 4H, CH₂—CH₂); 2.45 (m, 2H, CH₂—CO); 3.14 (m,2H, CH₂—N); 4.53 (s, 2H, CH₂Ph); 7.20 (m, 5H, H_(arom)).

NMR ¹³C (CDCl₃): 20.70; 22.60 (s, CH₂); 31.89 (s, CH₂—CO); 47.08; 49.91(s, CH₂—N); 127.15; 127.57; 128.37 (s, CH_(arom)); 136.56 (s, C_(ipso));170.77 (s, CO)

This example can also be implemented using a supported ylide as definedin the present invention, and more particularly with a polymer offormula (a) as defined above in which m>1.

EXAMPLE 3c

N-benzylation of Peptides

N-t-Boc-L-Leucine and the hydrochloride of the methyl ester ofL-phenylalanine, are coupled beforehand in the presence of a BrOPcoupling agent in order to obtain the corresponding dipeptide.

4 equivalents of ylide (5.85 mmoles) in 33 ml of THF are added slowly,at 25° C., to a solution of one equivalent of the dipeptide thusobtained (1.60 mmoles) in 9 ml of THF. The reaction mixture is agitatedat 25° C. for two hours, then 4 equivalents of benzyl bromide (5.85mmoles) are added. Agitation is maintained for 3 more hours. Thesupernatant solution is separated from the phosphonium salts formed byextraction with 60 ml of ether. After concentration, the oil obtained ispurified on a silica column (eluent: ether/hexane 50/50).

The monobenzylation product is obtained with a yield of 12% and thedibenzylation product is obtained with a yield of 28%. These compoundswere analyzed by gas chromatography coupled with electron impact massspectrometry.

EXAMPLE 3d

Re-use of a Supported Ylide for the N-functionalization of Norvalium

The polymer of Example 2c is washed several times in adichloromethane/acetonitrile mixture, dried under vacuum and re-used inthe N-benzylation reaction of norvalium under conditions as described inExample 3a. The N-benzylated compound is recovered with a yield of 79%,a yield comparable to that obtained in Example 3a₃.

What is claimed is:
 1. In a process for C-alkylation or N-alkylation, the improvement comprising conducting the C-alkylation or N-alkylation reaction in the presence of a slightly nucleophilic strong base of the following formula

wherein R′₁, R′₂ and R′₃ are individually selected from the group consisting of alkoxy of 1 to 6 carbon atoms and

are individually selected from the group consisting of unsubstituted or substituted alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl and aralkyl of 1 to 6 alkyl carbon atoms, the substituents being selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂ and dialkylamino of 1 to 6 alkyl carbon atoms, the aryl being selected from the group consisting of unsaturated monocyclic and condensed carbocyclic and heterocyclic with at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, R′₄ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms and R′₅ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and a polymeric support.
 2. The process of claim 1 wherein R′₁, R′₂ and R′₃ are individually


3. The process of claim 2 wherein R′₁, R′₂ and R′₃ are individually selected from the group consisting of dimethylamino, ethylmethylamino and diethylamino.
 4. The process of claim 1 wherein R′₄ is hydrogen or alkyl of 1 to 6 carbon atoms.
 5. The process of claim 1 wherein R′₄ is selected from the group consisting of hydrogen, methyl and ethyl.
 6. The process of claim 1 wherein R′₅ is alkyl of 1 to 6 carbon atoms or a polymeric support.
 7. The process of claim 1 wherein R′₅ is a polymeric support selected from the group consisting of a methacrylic polymer, an acrylic polymer and a polystyrenic polymer.
 8. The process of claim 7 wherein the polymeric support has the following formula

wherein n_(i), m_(i), and q_(i) are integers greater than or equal to
 1. 9. The process of claim 8 wherein m_(i) is
 1. 10. The process of claim 1 wherein the base is selected from the group consisting of tris(dimethylamino)-C-dimethylmethylene-phosphorane and styrene/divinylbenzene-tris(dimethylamino)-methylene phosphorane copolymer.
 11. The process of claim 1 wherein the reaction is a N-alkylation.
 12. The process of claim 11 wherein the N-alkylation is conducted with a member of the group consisting of lactams, succinimides, oligopeptides and benzodiazepines.
 13. The process of claim 1 wherein the reaction is a C-alkylation.
 14. The process of claim 13 wherein the C-alkylation is conducted with a member selected from the group consisting of lactams, succinimides, Schiff bases and benzodiazepines.
 15. A compound of the formula

wherein R₁, R₂, and R₃ are individually selected from the group consisting of alkoxy of 1 to 6 carbon atoms and

are individually selected from the group consisting of unsubstituted or substituted alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl and aralkyl of 1 to 6 alkyl carbon atoms, the substituents being selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂ and dialkylamino of 1 to 6 alkyl carbon atoms, the aryl being selected from the group consisting of unsaturated monocyclic and condensed carbocyclic and heterocyclic with at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, R₄ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms and R₅ is a polymeric support.
 16. A compound of claim 15 wherein R′₁, R′₂ and R′₃ are individually


17. A compound of claim 16 wherein

is selected from the group consisting of dimethylamino, ethylmethylamino and diethylamino.
 18. A compound of claim 15 wherein R₄ is hydrogen.
 19. A compound of claim 15 wherein R₅ is a polymeric support selected from the group consisting of methacylic polymer, acylic polymer and polystyrene polymer.
 20. A compound of claim 19 wherein the polymeric support is a polystyrene of the formula

wherein n_(i), m_(i), and q_(i) are integers of 1 or greater than
 1. 21. A process for the preparation of a compound of claim 15 comprising reacting a phosphine of the formula

wherein R₁, R₂ and R₃ are defined as in claim 15 with a compound of the formula

wherein R₄ and R₅ are defined as in claim 15 and Y is an anion to obtain a compound of the formula

and treating the obtained compound with a strong base to form the compound of claim
 15. 22. A compound of the following formula

wherein Y is an anion, R₁, R₂ and R₃ are individually selected from the group consisting of alkoxy of 1 to 6 carbon atoms and

R₄ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms, R₅ is a polymeric support, R′ and R″ are individually selected from the group consisting of unsubstituted or substituted alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 1 to 6 alkyl carbon atoms and aryl, the substituents being at least one member of the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂ and dialkylamino of 1 to 6 alkyl carbon atoms. 